The bacterium, Helicobacter pylori, is now well established as a major gastroduodenal pathogen, and more than 50% of the world population is infected with this organism which causes gastritis of varying severity. While no symptoms are apparent in a great proportion of infected persons, in a significant number of H. pylori infected persons overt disease may result. The majority (95%) of duodenal ulcers are associated with H. pylori infection; a causal role is shown by treatment studies which indicate that if the organisms can be eradicated at the time of ulcer healing then the ulcers do not recur--in contrast to 80% recurrence rate at one year in those who remain infected with the organisms. Furthermore, up to 80% of gastric ulcers are thought to be H. pylori associated (Blaser, 1992).
There is now increasing evidence of the harmful consequence of long term H. pylori infection. In countries such as China, Colombia and Japan the bacterium is picked up very early in life, and in these persons the gastritis slowly progresses until after 30-40 years of continual infection, severe gastric atrophy appears. Gastric atrophy is well documented as being the precursor lesion for gastric cancer, although the actual cancer that develops in an atrophied stomach is dependent on a myriad of other factors including diet. However, all the evidence to date would suggest that the cancer would not develop if it was possible to remove the H. pylori infection at an early age before the atrophy had developed (Parsonnet et al., 1991).
There is no laboratory animal model of H. pylori infection that can be used for large scale assessment of new anti-H. pylori therapies. However, a Helicobacter felis mouse model of gastric Helicobacter infection has been developed that has proved extremely useful in the screening of the potential of new antimicrobial therapeutic regimens. H. felis is a spiral shaped bacterium that is very closely related to H. pylori. This bacterium colonises the stomach of mice in a very similar way to H. pylori in the human, i.e. the main ecological niche is gastric mucus and the localisation of colonisation is antral dominant. In germfree mice, H. felis infection induces a gastritis that is very similar to the human H. pylori infection with a chronic inflammation accompanied by polymorphonuclear leucocyte infiltration. Infection with each organism results in the induction of a similar raised immune response against H. pylori and H. felis respectively (Lee et al., 1990).
The H. felis mouse model has proved to be very predictive of the efficacy of anti-H. pylori agents in humans. Thus, monotherapy with agents with high in vitro activity such as erythromycin show no significant in vivo effect against H. felis in mice, just as erythromycin has no anti-H. pylori effect in humans despite high antimicrobial effects in vitro. In contrast, the triple therapy regimens of a bismuth compound, metronidazole, and tetracycline or amoxycillin lead to a very high eradication rate in H. felis infected mice (Dick-Hegedus and Lee, 1991). Such triple therapies are the most successful human anti-H. pylori regimens, and at the present time are recommended as the first choice for anti-H. pylori therapy. However, established Helicobacter infections are difficult to treat, and current chemotherapeutic regimens remain suboptimal due to problems with efficacy, toxicity, drug resistance and reinfection (O'Connor, 1992).
Active immunisation of already infected patients has not been proven efficacious for any clinically manifest human infectious disease (Burke, 1992). Given that H. pylori infections persist for long periods, if not the life of the infected individual, despite the presence of a vigorous immune response that includes a high level of circulating IgG antibody in the serum and the demonstration of local specific IgA antibody in the gastric mucosa, it has been considered that active immunisation was unlikely to be effective in therapy (Goodwin, 1993). Indeed, Czinn et al. (1993) in proposing that oral vaccination may be a feasible approach for the prevention of H. pylori infection in humans (based on an evaluation of an oral immunisation protocol in the H. felis mouse model), suggested that once infection is established neither antibody nor antibiotics are very effective at eradication.
Varga et al. (1992) have reported that a H. pylori vaccine prepared from organisms derived from a patient, and injected parenterally into that patient, resulted in an allergic reaction and failure to eradicate the organism.
Surprisingly, it has now been discovered for the first time that there is indeed a therapeutic potential for active immunisation against gastric Helicobacter infection. Furthermore, it has been discovered that oral administration of H. pylori antigen, with a suitable mucosal adjuvant, does not result in allergic or hypersensitivity symptoms, but results in suppression or eradication of the infecting organisms from the gastric mucosa.